Salt forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-hepatonic acid

ABSTRACT

Novel salt forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid characterized by their X-ray powder diffraction pattern and solid-state NMR spectra are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as agents for treating hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia, and Alzheimer&#39;s Disease.

This application is a divisional application of U.S. Ser. No. 15/061,931filed Mar. 4, 2016, now pending which is a divisional application ofU.S. Ser. No. 14/716,361 filed May 19, 2015, now U.S. Pat. No. 9,309,195which is a divisional application of U.S. Ser. No. 14/340,067 filed Jul.24, 2014, now U.S. Pat. No. 9,073,852 which is a divisional applicationof U.S. Ser. No. 14/016,839 filed Sep. 3, 2013, now U.S. Pat. No.8,822,703 which is a divisional application of U.S. Ser. No. 13/537,432filed Jun. 29, 2012, now U.S. Pat. No. 8,552,207 which is a divisionalapplication of U.S. Ser. No. 12/966,488 filed Dec. 13, 2010, now U.S.Pat. No. 8,236,966 which is a divisional application of U.S. Ser. No.11/579,656 filed on Mar. 12, 2008, now U.S. Pat. No. 7,875,731 which isa 371 application of PCT/1B2005/001237 filed on Apr. 25, 2005, whichclaims benefit of provisional application U.S. Ser. No. 60/568,379 filedon May 5, 2004, all of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to novel salt forms of atorvastatin whichis known by the chemical name[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, useful as pharmaceutical agents, to methods for their productionand isolation to pharmaceutical compositions which include thesecompounds and a pharmaceutically acceptable carrier, as well as methodsof using such compositions to treat subjects, including human subjects,suffering from hyperlipidemia, hypercholesterolemia, benign prostatichyperplasia, osteoporosis, and Alzheimer's Disease.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

Atorvastatin calcium is currently sold as Lipitor® having the chemicalname[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate and the formula:

The nonproprietary name designated by USAN (United States Adopted Names)is atorvastatin calcium and by INN (International Nonproprietary Name)is atorvastatin. Under the established guiding principles of USAN, thesalt is included in the name whereas under INN guidelines, a saltdescription is not included in the name.

Atovastatin calcium is a selective, competitive inhibitor of HMG-CoAreductase. As such, atorvastatin calcium is a potent lipid loweringcompound and is thus useful as a hypolipidemic and/orhypocholesterolemic agent, as well as in the treatment of osteoporosis,benign prostatic hyperplasia, and Alzheimer's disease.

A number of patents have issued disclosing atorvastatin calcium,formulations of atorvastatin calcium, as well as processes and keyintermediates for preparing atorvastatin calcium. These include: U.S.Pat. Nos. 4,681,893; 5,273,995; 5,003,080; 5,097,045; 5,103,024;5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793;5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981;5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,998,633; 6,087,511;6,126,971; 6,433,213; and 6,476,235, which are herein incorporated byreference.

Atorvastatin calcium can exist in crystalline, liquid-crystalline,non-crystalline and amorphous forms.

Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat.Nos. 5,969,156, 6,121,461, and 6,605,729 which are herein incorporatedby reference.

Additionally, a number of published International Patent Applicationshave disclosed crystalline forms of atorvastatin calcium, as well asprocesses for preparing amorphous atorvastatin calcium. These include:WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO02/057274; WO 02/059087; WO 02/072073; WO 02/083637; WO 02/083638; andWO 02/089788.

Atorvastatin is prepared as its calcium salt, i.e.,[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-1-heptanoicacid calcium salt (2:1). The calcium salt is desirable since it enablesatorvastatin to be conveniently formulated in, for example, tablets,capsules, lozenges, powders, and the like for oral administration.

U.S. Pat. No. 5,273,995 discloses the mono-sodium, mono-potassium,hemi-calcium, N-methylglucamine, hemi-magnesium, hemi-zinc, and the1-deoxy-1-(methylamino)-D-glucitol (N-methylglucamine) salts ofatorvastatin.

Also, atorvastatin free acid, disclosed in U.S. Pat. No. 5,273,995, canbe used to prepare these salts of atorvastatin.

Additionally, U.S. Pat. No. 6,583,295 B1 discloses a series of aminesalts of HMG-CoA reductase inhibitors which are used in a process forisolation and/or purification of these HMG-CoA reductase. The tertiarybutylamine and dicyclohexylamine salts of atorvastatin are disclosed.

We have now surprisingly and unexpectedly found novel salt forms ofatorvastatin including salts with ammonium, benethamine, benzathine,dibenzylamine, diethylamine, L-lysine, morpholine, olamine, piperazine,and 2-amino-2-methylpropan-1-ol which have desirable properties.Additionally, we have surprisingly and unexpectedly found novelcrystalline forms of atorvastatin which include salts with erbumine andsodium which have desirable properties. As such, these salt forms arepharmaceutically acceptable and can be used to prepare pharmaceuticalformulations. Thus, the present invention provides basic salts ofatorvastatin that are pure, have good stability, and have advantageousformulation properties compared to prior salt forms of atorvastatin.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the invention is directed to atorvastatinammonium and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >30% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>30%) 3.5 49.0 4.4 34.8 7.4 36.5 7.8 58.08.8 53.9 9.3 44.1 9.9 43.8 10.6 80.3 12.4 35.1 14.1 30.1 16.8 54.5 18.356.2 19.0 67.8 19.5 100.0 20.3 81.4 21.4 69.0 21.6 63.8 23.1 65.5 23.963.8 24.8 69.0

In a second aspect, the invention is directed to Form A atorvastatinbenethamine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >8% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>8%) 4.7 42.2 5.3 21.7 6.0 12.9 7.8 9.68.9 53.3 9.5 84.4 10.5 10.6 12.0 11.5 13.8 12.1 14.3 13.3 15.6 20.1 16.724.6 16.9 19.9 17.6 52.7 17.8 53.1 18.1 59.7 18.8 100.0 19.1 39.1 19.942.4 21.3 36.2 21.9 22.8 22.7 19.8 23.6 52.4 24.3 23.5 25.9 23.5 26.336.2 27.0 13.5 27.9 11.8 28.8 9.4 29.6 9.8

In a third aspect, the invention is directed to Form A atorvastatinbenethamine and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance (SSNMR) spectrum whereinchemical shift is expressed in parts per million (ppm):

Peak # ppm* 1 180.1 2 178.8 3 165.1 4 164.1 5 162.8 6 161.7 7 160.7 8140.6 9 139.6 10 137.9 11 136.1 12 133.0 13 129.6 14 127.3 15 126.4 16125.4 17 123.1 18 122.5 19 121.6 20 121.1 21 119.9 22 116.4 23 115.4 24114.5 25 114.0 26 66.0 27 65.5 28 64.6 29 53.6 30 51.5 31 51.0 32 47.833 44.6 34 43.3 35 41.4 36 40.9 37 38.5 38 37.7 39 36.8 40 34.0 41 32.742 26.5 43 25.1 44 23.5 45 23.1 46 19.7 47 19.1 *Values in ppm withrespect to trimethylsilane (TMS) at 0 ppm; referenced using an externalsample of adamantane, setting is upfield resonance to 29.5 ppm.

In a fourth aspect, the present invention is directed to Form Aatorvastatin benethamine and hydrates thereof characterized by thefollowing solid-state ¹⁹F nuclear magnetic resonance spectrum whereinchemical shift is expressed in parts per million:

Peak # ppm* 1 −113.2 2 −114.2 *Values in ppm with respect to CCl₃F at 0ppm, referenced using an external standard of trifluoroacetic acid (50%V/V in water) at −76.54 ppm.

In a fifth aspect, the invention is directed to Form B atorvastatinbenethamine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >6% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>6%) 4.1 9.8 5.0 11.3 5.8 8.8 7.1 10.4 8.413.3 8.9 53.2 10.0 8.1 11.6 13.6 12.6 16.6 14.4 46.3 14.8 13.5 16.5 15.417.7 23.6 18.6 20.2 20.2 100.0 21.4 30.6 21.6 24.7 22.3 5.9 22.7 6.323.4 8.4 23.6 12.8 25.0 10.2 25.2 12.2 25.9 19.2 26.2 30.1 28.0 6.9 28.35.4 29.3 6.4 29.7 5.9 31.8 5.3 33.5 12.1 35.2 6.6 35.8 5.9

In a sixth aspect, the invention is directed to Form B atorvastatinbenethamine and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Peak # ppm* 1 179.4 2 165.6 3 162.4 4 140.1 5 138.6 6 133.6 7 132.8 8129.9 9 128.2 10 125.7 11 123.6 12 114.8 13 69.6 14 69.0 15 52.3 16 49.817 43.1 18 42.2 19 39.6 20 38.9 21 31.5 22 26.5 23 23.5 24 19.6 *Valuesin ppm with respect to trimethylsilane (TMS) at 0 ppm; referenced usingan external sample of adamantane, setting is upfield resonance to 29.5ppm.

In a seventh aspect, the invention is directed to Form B atorvastatinbenethamine and hydrates thereof characterized by the followingsolid-state ¹⁹F nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Peak # ppm* 1 −113.7 2 −114.4 *Values in ppm with respect to CCl₃F at 0ppm, referenced using an external standard of trifluoroacetic acid (50%V/V in water) at −76.54 ppm.

In a eighth aspect, the invention is directed to Form A atorvastatinbenzathine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >12% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>12%) 9.1 97.5 14.0 40.3 15.1 13.8 15.513.7 16.1 15.3 16.4 16.8 18.2 40.0 19.1 58.5 19.6 18.1 20.5 100.0 21.366.3 22.1 15.5 22.5 21.7 23.0 43.8 25.2 18.8 25.9 12.9 26.1 15.6 26.514.4 28.0 14.2 28.6 17.1

In a ninth aspect, the invention is directed to Form B atorvastatinbenzathine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >9% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>9%) 8.3 100.0 9.1 9.4 10.2 62.6 11.7 9.113.2 10.2 14.4 21.1 15.8 18.1 16.6 20.0 17.1 14.8 18.6 34.0 19.1 40.719.4 23.0 19.7 14.8 20.6 24.0 20.9 13.1 21.4 28.8 21.8 29.3 22.3 24.922.6 29.2 23.3 46.1 23.5 31.3 24.3 11.0 25.0 18.9 26.5 14.8 26.8 11.627.4 13.2 27.9 12.3 28.2 9.3 28.9 9.3 29.1 9.8 29.7 10.9

In a tenth aspect, the invention is directed to Form C atorvastatinbenzathine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >13% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>13%) 3.9 59.5 6.9 23.3 7.9 30.5 9.7 70.611.9 100.0 12.8 17.8 13.2 41.4 15.5 15.3 16.3 13.1 16.8 17.4 17.2 39.518.9 18.4 19.5 31.5 19.9 31.7 20.4 58.2 20.7 43.9 21.4 29.2 23.0 19.023.4 18.7 24.0 26.6 24.3 33.6 24.6 41.4 25.9 21.5 26.2 28.4

In an eleventh aspect, the invention is directed to atorvastatindibenzylamine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >8% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>8%) 4.6 10.6 8.3 50.8 9.6 13.8 9.8 10.010.3 14.9 10.4 12.1 10.6 19.8 11.8 13.9 12.4 7.7 13.3 10.0 14.5 10.214.9 11.6 15.9 11.8 16.7 10.4 17.4 23.6 18.4 19.7 18.7 38.5 19.4 24.219.8 48.0 20.7 100.0 21.3 56.4 21.6 26.7 22.1 13.4 22.5 21.9 23.0 9.723.4 29.5 23.7 29.7 24.3 11.0 24.6 13.6 25.1 13.0 25.8 31.9 26.7 8.528.0 10.8 29.2 12.2 33.4 9.8 34.6 8.1 34.8 9.1

In a twelfth aspect, the invention is directed to atorvastatindibenzylamine and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Peak # ppm* 1 179.1 2 166.2 3 163.1 4 160.8 5 140.6 6 135.2 7 134.3 8133.4 9 131.9 10 131.1 11 129.4 12 128.3 13 125.6 14 124.2 15 122.9 16119.7 17 115.4 18 69.7 19 68.6 20 52.6 21 51.3 22 43.0 23 41.9 24 38.825 38.2 26 26.7 27 23.3 28 20.0 *Values in ppm with respect totrimethylsilane (TMS) at 0 ppm; referenced using an external sample ofadamantane, setting is upfield resonance to 29.5 ppm.

In a thirteenth aspect, the invention is directed to atorvastatindibenzylamine and hydrates thereof characterized by the followingsolid-state ¹⁹F nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Peak # ppm* 1 −107.8 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

In a fourteenth aspect, the invention is directed to Form A atorvastatindiethylamine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >20% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>20%) 7.0 53.0 8.2 32.0 10.8 59.3 12.336.0 13.3 60.8 14.4 56.0 16.1 35.5 16.5 39.3 17.0 40.0 18.2 49.3 18.4100.0 19.4 23.0 20.0 20.5 21.0 54.5 21.7 24.5 22.3 30.5 23.0 68.8 24.325.5 25.1 38.5 25.4 26.9 26.3 41.3 26.8 21.8 28.4 23.8

In an fifteenth aspect, the invention is directed to Form B atorvastatindiethylamine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >8% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>8%) 6.1 8.3 7.0 10.6 8.3 26.0 10.8 8.511.5 21.4 12.2 28.2 12.5 12.7 13.4 16.5 14.5 10.0 15.3 34.2 16.1 17.116.6 12.8 16.8 16.6 17.4 17.3 17.9 8.1 18.4 12.8 18.7 8.5 19.3 52.2 20.521.4 21.0 100.0 22.3 13.0 23.2 34.2 24.6 23.7 25.4 8.2 25.9 8.1 26.416.9 27.6 25.6 29.2 10.6 31.2 8.5 32.8 9.1

In an sixteenth aspect, the invention is directed to atorvastatinerbumine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >6% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>6%) 5.4 11.9 7.3 12.0 9.5 100.0 12.6 14.315.2 15.6 16.6 13.7 17.8 21.0 18.6 20.2 19.2 77.6 20.0 28.3 20.4 8.220.9 22.3 21.6 14.3 22.2 26.6 22.4 13.3 22.6 14.5 23.7 8.7 24.2 31.625.0 15.5 26.5 12.3 28.2 7.9 29.5 6.3 30.6 6.5

In a seventeenth aspect, the invention is directed to atorvastatinerbumine and hydrates thereof characterized by the following solid-state¹³C nuclear magnetic resonance spectrum wherein chemical shift isexpressed in parts per million:

Peak # ppm* 1 179.3 2 164.5 3 163.0 4 160.9 5 141.3 6 140.9 7 135.3 8134.5 9 132.8 10 129.0 11 127.7 12 124.5 13 121.8 14 120.2 15 116.5 16115.5 17 112.4 18 71.3 19 50.3 20 47.7 21 42.6 22 41.0 23 28.5 24 26.425 22.6 26 21.6 *Values in ppm with respect to trimethylsilane (TMS) at0 ppm; referenced using an external sample of adamantane, setting isupfield resonance to 29.5 ppm.

In a eighteenth aspect, the invention is directed to atorvastatinerbumine and hydrates thereof characterized by the following solid-state¹⁹F nuclear magnetic resonance spectrum wherein chemical shift isexpressed in parts per million:

Peak # ppm* 1 −110.4 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

In a nineteenth aspect, the invention is directed to atorvastatinL-lysine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >40% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>40%) 6.7 100.0 9.5 62.1 9.8 74.3 17.180.4 18.7 86.5 19.6 76.8 21.1 77.1 22.1 72.1 22.5 77.9 24.0 59.5

In a twentieth aspect, the invention is directed to atorvastatinmorpholine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >9% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>9%) 4.8 15.9 5.7 10.7 6.4 11.6 8.6 9.29.7 52.5 12.8 6.8 14.1 10.3 14.6 22.5 16.0 42.1 16.3 26.7 16.5 21.3 17.319.6 17.5 29.3 18.1 16.5 18.9 46.1 19.2 27.3 19.6 85.9 19.9 19.8 20.842.2 21.2 16.9 22.1 89.9 23.1 19.6 23.9 100.0 24.6 26.0 25.0 39.0 25.711.0 27.0 14.1 28.1 10.1 28.5 25.8 29.6 11.8 30.1 9.9 30.9 13.4 31.014.1 32.0 13.0 32.4 16.5 33.4 14.1 33.9 11.0 34.6 18.0 35.4 14.3 36.818.2 37.6 11.4

In a twenty-first aspect, the invention is directed to atorvastatinmorpholine and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Peak # ppm* 1 179.3 2 165.9 3 162.7 4 160.5 5 139.6 6 137.8 7 134.3 8131.2 9 129.6 10 128.7 11 127.4 12 122.9 13 120.8 14 117.9 15 116.3 1670.8 17 69.5 18 63.4 19 42.4 20 41.2 21 40.5 22 24.8 23 20.6 *Values inppm with respect to trimethylsilane (TMS) at 0 ppm; referenced using anexternal sample of adamantane, setting is upfield resonance to 29.5 ppm.

In a twenty-second aspect, the invention is directed to atorvastatinmorpholine and hydrates thereof characterized by the following ¹⁹Fnuclear magnetic resonance spectrum wherein chemical shift is expressedin parts per million:

Peak # ppm* 1 −117.6 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

In a twenty-third aspect, the invention is directed to atorvastatinolamine and hydrates thereof characterized by the following x-ray powderdiffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >15% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>15%) 8.5 100.0 9.8 74.7 11.4 17.3 12.015.6 16.3 27.7 17.4 43.9 18.6 85.5 19.6 45.8 20.1 43.9 20.9 96.0 21.431.6 22.0 30.5 22.5 66.1 22.8 35.6 23.5 20.5 24.1 42.7 25.1 23.3 25.925.0 26.2 33.1 27.8 19.3 28.8 27.5 29.6 20.0 31.7 20.5 37.7 22.5

In a twenty-fourth aspect, the invention is directed to atorvastatinolamine and hydrates thereof characterized by the following ¹³C nuclearmagnetic resonance spectrum wherein chemical shift is expressed in partsper million:

Peak # ppm* 1 182.0 2 178.9 3 165.4 4 161.6 5 159.5 6 137.4 7 134.8 8133.8 9 131.0 10 128.7 11 128.0 12 127.0 13 123.1 14 122.6 15 121.9 16120.9 17 120.1 18 117.3 19 115.6 20 114.3 21 66.5 22 66.0 23 65.2 2458.5 25 58.2 26 51.1 27 47.8 28 46.0 29 43.9 30 42.4 31 41.3 32 40.6 3339.8 34 25.7 35 23.1 36 21.1 37 20.7 *Values in ppm with respect totrimethylsilane (TMS) at 0 ppm; referenced using an external sample ofadamantane, setting is upfield resonance to 29.5 ppm.

In a twenty-fifth aspect, the invention is directed to atorvastatinolamine and hydrates thereof characterized by the following ¹⁹F nuclearmagnetic resonance spectrum wherein chemical shift is expressed in partsper million:

Peak # ppm* 1 −118.7 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

In a twenty-sixth aspect, the invention is directed to atorvastatinpiperazine and hydrates thereof characterized by the following x-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >20% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>20%) 4.4 20.4 7.8 25.5 9.3 27.2 11.8 29.713.2 22.9 16.1 30.0 17.7 30.9 19.7 100.0 20.4 55.0 22.2 31.9 22.9 36.223.8 30.7 26.4 32.6

In a twenty-seventh aspect, the invention is directed to atorvastatinsodium and hydrates thereof characterized by the following x-ray powderdiffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >25% measured on a Bruker D5000diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>25%) 3.4 57.8 4.1 29.2 4.9 53.0 5.6 32.46.8 25.2 7.6 68.5 8.0 75.7 8.5 42.0 9.9 66.1 10.4 51.5 12.8 25.5 18.9100.0 19.7 64.5 21.2 32.8 22.1 33.3 22.9 45.4 23.3 43.6 24.0 42.7 25.226.1

In a twenty-eighth aspect, the invention is directed to atorvastatin2-amino-2-methylpropan-1-ol and hydrates thereof characterized by thefollowing x-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >20% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Degree Intensity 2θ (>20%) 4.2 95.2 6.0 59.9 6.2 43.7 8.3 26.311.5 20.9 12.5 36.5 12.6 31.1 16.0 44.4 17.5 54.3 18.3 52.8 18.8 34.019.4 55.3 19.7 100.0 21.3 26.7 22.0 31.3 22.8 21.7 23.4 29.7 23.8 28.6

In a twenty-ninth aspect, the invention is directed to atorvastatin2-amino-2-methylpropan-1-ol and hydrates thereof characterized by thefollowing ¹³C nuclear magnetic resonance spectrum wherein chemical shiftis expressed in parts per million:

Peak # ppm* 1 179.8 2 166.3 3 163.3 4 161.5 5 161.2 6 140.5 7 139.5 8134.4 9 132.3 10 131.6 11 129.8 12 128.1 13 126.1 14 125.1 15 122.2 16120.7 17 116.4 18 114.0 19 113.4 20 72.6 21 71.4 22 67.6 23 66.3 24 64.725 64.4 26 53.1 27 46.9 28 43.9 29 43.5 30 42.7 31 39.7 32 36.1 33 26.834 26.3 35 24.3 36 23.8 37 23.1 38 22.0 39 20.4 *Values in ppm withrespect to trimethylsilane (TMS) at 0 ppm; referenced using an externalsample of adamantane, setting is upfield resonance to 29.5 ppm.

In a thirtieth aspect, the invention is directed to atorvastatin2-amino-2-methylpropan-1-ol and hydrates thereof characterized by thefollowing ¹⁹F nuclear magnetic resonance spectrum wherein chemical shiftis expressed in parts per million:

Peak # ppm* 1 −113.6 2 −116.5 *Values in ppm with respect to CCl₃F at 0ppm, referenced using an external standard of trifluoroacetic acid (50%V/V in water) at −76.54 ppm.

As inhibitors of HMG-CoA reductase, the novel salt forms of atorvastatinare useful as hypolipidemic and hypocholesterolemic agents, as well asagents in the treatment of osteoporosis, benign prostatic hyperplasia,and Alzheimer's Disease.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of an atorvastatinsalt in unit dosage form in the treatment methods mentioned above.Finally, the present invention is directed to methods for production ofsalt forms of atorvastatin.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further described by the following nonlimiting exampleswhich refer to the accompanying FIGS. 1 to 30, short particulars ofwhich are given below.

FIG. 1 Diffractogram of atorvastatin ammonium carried out on a BrukerD5000 diffractometer.

FIG. 2 Diffractogram of Form A atorvastatin benethamine carried out on aBruker D5000 diffractometer.

FIG. 3 Solid-state ¹³C nuclear magnetic resonance spectrum of Form Aatorvastatin benethamine.

FIG. 4 Solid-state ¹⁹F nuclear magnetic resonance spectrum of Form Aatorvastatin benethamine.

FIG. 5 Diffractogram of Form B atorvastatin benethamine carried out on aBruker D5000 diffractometer.

FIG. 6 Solid-state ¹³C nuclear magnetic resonance spectrum of Form Batorvastatin benethamine.

FIG. 7 Solid-state ¹⁹F nuclear magnetic resonance spectrum of Form Batorvastatin benethamine.

FIG. 8 Diffractogram of Form A atorvastatin benzathine carried out on aBruker D5000 diffractometer.

FIG. 9 Diffractogram of Form B atorvastatin benzathine carried out on aBruker D5000 diffractometer.

FIG. 10 Diffractogram of Form C atorvastatin benzathine carried out on aBruker D5000 diffractometer.

FIG. 11 Diffractogram of atorvastatin dibenzylamine carried out on aBruker D5000 diffractometer.

FIG. 12 Solid-state ¹³C nuclear magnetic resonance spectrum ofatorvastatin dibenzylamine.

FIG. 13 Solid-state ¹⁹F nuclear magnetic resonance spectrum ofatorvastatin dibenzylamine.

FIG. 14 Diffractogram of Form A atorvastatin diethylamine carried out ona Bruker D5000 diffractometer.

FIG. 15 Diffractogram of Form B atorvastatin diethylamine carried out ona Bruker D5000 diffractometer.

FIG. 16 Diffractogram of atorvastatin erbumine carried out on a BrukerD5000 diffractometer.

FIG. 17 Solid-state ¹³C nuclear magnetic resonance spectrum ofatorvastatin erbumine.

FIG. 18 Solid-state ¹⁹F nuclear magnetic resonance spectrum ofatorvastatin erbumine.

FIG. 19 Diffractogram of atorvastatin L-lysine carried out on a BrukerD5000 diffractometer.

FIG. 20 Diffractogram of atorvastatin morpholine carried out on a BrukerD5000 diffractometer.

FIG. 21 Solid-state ¹³C nuclear magnetic resonance spectrum ofatorvastatin morpholine.

FIG. 22 Solid-state ¹⁹F nuclear magnetic resonance spectrum ofatorvastatin morpholine.

FIG. 23 Diffractogram of atorvastatin olamine carried out on a BrukerD5000 diffractometer.

FIG. 24 Solid-state ¹³C nuclear magnetic resonance spectrum ofatorvastatin olamine.

FIG. 25 Solid-state ¹⁹F nuclear magnetic resonance spectrum ofatorvastatin olamine.

FIG. 26 Diffractogram of atorvastatin piperazine carried out on a BrukerD5000 diffractometer.

FIG. 27 Diffractogram of atorvastatin sodium carried out on a BrukerD5000 diffractometer.

FIG. 28 Diffractogram of atorvastatin 2-amino-2-methylpropan-1-olcarried out on a Bruker D5000 diffractometer.

FIG. 29 Solid-state ¹³C nuclear magnetic resonance spectrum ofatorvastatin 2-amino-2-methylpropan-1-ol.

FIG. 30 Solid-state ¹⁹F nuclear magnetic resonance spectrum ofatorvastatin 2-amino-2-methylpropan-1-ol.

DETAILED DESCRIPTION OF THE INVENTION

The novel salt forms of atorvastatin may be characterized by their x-raypowder diffraction patterns and/or by their solid-state nuclear magneticresonance spectra.

Powder X-ray Diffraction

Atorvastatin salts were characterized by their powder x-ray diffractionpatterns. Thus, the x-ray diffraction pattern was carried out on aBruker D5000 diffractometer using copper radiation (wavelength1:1.54056). The tube voltage and amperage were set to 40 kV and 50 mA,respectively. The divergence and scattering slits were set at 1 mm, andthe receiving slit was set at 0.6 mm. Diffracted radiation was detectedby a Kevex PSI detector. A theta-two theta continuous scan at 2.4°/min(1 sec/0.04° step) from 3.0 to 40° 2θ was used. An alumina standard wasanalyzed to check the instrument alignment. Data were collected andanalyzed using Bruker axis software Version 7.0. Samples were preparedby placing them in a quartz holder. It should be noted that BrukerInstruments purchased Siemans; thus, Bruker D5000 instrument isessentially the same as a Siemans D5000.

The following tables list the 2θ and intensities of lines for theatorvastatin salts and hydrates thereof. Additionally, there are tableswhich list individual 2θ peaks for the atorvastatin salts and hydratesthereof. In cases were there are two or more crystalline forms of anatorvastatin salt or hydrate thereof, each form can be identified anddistinguished from the other crystalline form by either a single x-raydiffraction line, a combination of lines, or a pattern that is differentfrom the x-ray powder diffraction of the other forms.

Table 1 lists the 2θ and relative intensities of all lines that have arelative intensity of >30% in the sample for atorvastatin ammonium andhydrates thereof:

TABLE 1 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES INATORVASTATIN AMMONIUM AND HYDRATES THEREOF Relative Degree Intensity 2θ(>30%) 3.5 49.0 4.4 34.8 7.4 36.5 7.8 58.0 8.8 53.9 9.3 44.1 9.9 43.810.6 80.3 12.4 35.1 14.1 30.1 16.8 54.5 18.3 56.2 19.0 67.8 19.5 100.020.3 81.4 21.4 69.0 21.6 63.8 23.1 65.5 23.9 63.8 24.8 69.0

Table 2 lists individual peaks for atorvastatin ammonium and hydratesthereof:

TABLE 2 ATORVASTATIN AMMONIUM AND HYDRATES THEREOF DEGREE 2θ 7.8 8.8 9.39.9 10.6 12.4 19.5

Table 3 lists the 2θ and relative intensities of all lines that have arelative intensity of >8% in the sample for atorvastatin benethamineForms A and B and hydrates thereof:

TABLE 3 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN BENETHAMINE, FORMS A AND B AND HYDRATES THEREOF Form A FormB Relative Relative Degree Intensity Degree Intensity 2θ (>8%) 2θ (>6%)4.7 42.2 4.1 9.8 5.3 21.7 5.0 11.3 6.0 12.9 5.8 8.8 7.8 9.6 7.1 10.4 8.953.3 8.4 13.3 9.5 84.4 8.9 53.2 10.5 10.6 10.0 8.1 12.0 11.5 11.6 13.613.8 12.1 12.6 16.6 14.3 13.3 14.4 46.3 15.6 20.1 14.8 13.5 16.7 24.616.5 15.4 16.9 19.9 17.7 23.6 17.6 52.7 18.6 20.2 17.8 53.1 20.2 100.018.1 59.7 21.4 30.6 18.8 100.0 21.6 24.7 19.1 39.1 22.3 5.9 19.9 42.422.7 6.3 21.3 36.2 23.4 8.4 21.9 22.8 23.6 12.8 22.7 19.8 25.0 10.2 23.652.4 25.2 12.2 24.3 23.5 25.9 19.2 25.9 23.5 26.2 30.1 26.3 36.2 28.06.9 27.0 13.5 28.3 5.4 27.9 11.8 29.3 6.4 28.8 9.4 29.7 5.9 29.6 9.831.8 5.3 33.5 12.1 35.2 6.6 35.8 5.9

Table 4 lists individual 2θ peaks for atorvastatin benethamine, Forms Aand B and hydrates thereof.

TABLE 4 FORMS A and B ATORVASTATIN BENETHAMINE AND HYDRATES THEREOF FormA Form B Degree Degree 2θ 2θ 4.7 5.0 5.3 7.1 9.5 8.4 12.0 10.0 15.6 11.618.1 12.6 19.9 14.8 20.2

Table 5 lists the 2θ and relative intensities of all lines that have arelative intensity of >9% in the sample for atorvastatin benzathineForms A, B, and C and hydrates thereof:

TABLE 5 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN BENZATHINE, FORMS A, B, AND C AND HYDRATES THEREOF Form AForm B Form C Relative Relative Relative Degree Intensity DegreeIntensity Degree Intensity 2θ (>12%) 2θ (>9%) 2θ (>13%) 9.1 97.5 8.3100.0 3.9 59.5 14.0 40.3 9.1 9.4 6.9 23.3 15.1 13.8 10.2 62.6 7.9 30.515.5 13.7 11.7 9.1 9.7 70.6 16.1 15.3 13.2 10.2 11.9 100.0 16.4 16.814.4 21.1 12.8 17.8 18.2 40.0 15.8 18.1 13.2 41.4 19.1 58.5 16.6 20.015.5 15.3 19.6 18.1 17.1 14.8 16.3 13.1 20.5 100.0 18.6 34.0 16.8 17.421.3 66.3 19.1 40.7 17.2 39.5 22.1 15.5 19.4 23.0 18.9 18.4 22.5 21.719.7 14.8 19.5 31.5 23.0 43.8 20.6 24.0 19.9 31.7 25.2 18.8 20.9 13.120.4 58.2 25.9 12.9 21.4 28.8 20.7 43.9 26.1 15.6 21.8 29.3 21.4 29.226.5 14.4 22.3 24.9 23.0 19.0 28.0 14.2 22.6 29.2 23.4 18.7 28.6 17.123.3 46.1 24.0 26.6 23.5 31.3 24.3 33.6 24.3 11.0 24.6 41.4 25.0 18.925.9 21.5 26.5 14.8 26.2 28.4 26.8 11.6 27.4 13.2 27.9 12.3 28.2 9.328.9 9.3 29.1 9.8 29.7 10.9

Table 6 lists individual 2θ peaks for atorvastatin benzathine, Forms A,B, and C and hydrates thereof.

TABLE 6 FORMS A, B, and C ATORVASTATIN BENZATHINE AND HYDRATES THEREOFForm A Form B Form C Degree Degree Degree 2θ 2θ 2θ 14.0 8.3 3.9 15.110.2 6.9 14.4 7.9 15.8 9.7 18.6 12.8 21.8 23.3

Table 7 lists the 2θ and relative intensities of all lines that have arelative intensity of >8% in the sample for atorvastatin dibenzylamineand hydrates thereof:

TABLE 7 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN DIBENZYLAMINE AND HYDRATES THEREOF Relative DegreeIntensity 2θ (>8%) 4.6 10.6 8.3 50.8 9.6 13.8 9.8 10.0 10.3 14.9 10.412.1 10.6 19.8 11.8 13.9 12.4 7.7 13.3 10.0 14.5 10.2 14.9 11.6 15.911.8 16.7 10.4 17.4 23.6 18.4 19.7 18.7 38.5 19.4 24.2 19.8 48.0 20.7100.0 21.3 56.4 21.6 26.7 22.1 13.4 22.5 21.9 23.0 9.7 23.4 29.5 23.729.7 24.3 11.0 24.6 13.6 25.1 13.0 25.8 31.9 26.7 8.5 28.0 10.8 29.212.2 33.4 9.8 34.6 8.1 34.8 9.1

Table 8 lists the individual 2θ peaks for atorvastatin dibenzylamine andhydrates thereof:

TABLE 8 ATORVASTATIN DIBENZYLAMINE AND HYDRATES THEREOF Degree 2θ 8.318.7 19.8 20.7 21.3 25.8

Table 9 lists the 2θ and relative intensities of all lines that have arelative intensity of >8% in the sample for atorvastatin diethylamineForms A and B and hydrates thereof:

TABLE 9 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN DIETHYLAMINE, FORMS A AND B AND HYDRATES THEREOF Form AForm B Relative Relative Degree Intensity Degree Intensity 2θ (>20%) 2θ(>8%) 7.0 53.0 6.1 8.3 8.2 32.0 7.0 10.6 10.8 59.3 8.3 26.0 12.3 36.010.8 8.5 13.3 60.8 11.5 21.4 14.4 56.0 12.2 28.2 16.1 35.5 12.5 12.716.5 39.3 13.4 16.5 17.0 40.0 14.5 10.0 18.2 49.3 15.3 34.2 18.4 100.016.1 17.1 19.4 23.0 16.6 12.8 20.0 20.5 16.8 16.6 21.0 54.5 17.4 17.321.7 24.5 17.9 8.1 22.3 30.5 18.4 12.8 23.0 68.8 18.7 8.5 24.3 25.5 19.352.2 25.1 38.5 20.5 21.4 25.4 26.9 21.0 100.0 26.3 41.3 22.3 13.0 26.821.8 23.2 34.2 28.4 23.8 24.6 23.7 25.4 8.2 25.9 8.1 26.4 16.9 27.6 25.629.2 10.6 31.2 8.5 32.8 9.1

Table 10 lists individual 2θ peaks for atorvastatin diethylamine, FormsA, B, and C and hydrates thereof.

TABLE 10 FORMS A AND B ATORVASTATIN DIETHYLAMINE AND HYDRATES THEREOFForm A Form B Degree Degree 2θ 2θ 17.0 6.1 18.2 11.5 20.0 15.3 21.7 17.423.0 20.5 23.2 27.6

Table 11 lists the 2θ and relative intensities of all lines that have arelative intensity >6% in the sample for atorvastatin erbumine andhydrates thereof:

TABLE 11 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN ERBUMINE AND HYDRATES THEREOF Relative Degree Intensity 2θ(>6%) 5.4 11.9 7.3 12.0 9.5 100.0 12.6 14.3 15.2 15.6 16.6 13.7 17.821.0 18.6 20.2 19.2 77.6 20.0 28.3 20.4 8.2 20.9 22.3 21.6 14.3 22.226.6 22.4 13.3 22.6 14.5 23.7 8.7 24.2 31.6 25.0 15.5 26.5 12.3 28.2 7.929.5 6.3 30.6 6.5

Table 12 lists individual 2θ peaks for atorvastatin erbumine andhydrates thereof:

TABLE 12 ATORVASTATIN ERBUMINE AND HYDRATES THEREOF Degree 2θ 5.4 7.39.5 17.8 19.2 20.0 22.2 24.2

Table 13 lists 2θ and relative intensities of all lines that have arelative intensity of >40% in the sample for atorvastatin L-lysine andhydrates thereof:

TABLE 13 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN L-LYSINE AND HYDRATES THEREOF Relative Degree Intensity 2θ(>40%) 6.7 100.0 9.5 62.1 9.8 74.3 17.1 80.4 18.7 86.5 19.6 76.8 21.177.1 22.1 72.1 22.5 77.9 24.0 59.5

Table 14 lists individual 2θ peaks for atorvastatin L-Lysine andhydrates thereof:

TABLE 14 ATORVASTATIN L-LYSINE AND HYDRATES THEREOF Degree 2θ 6.7 9.817.1 24.0

Table 15 lists the 2θ and relative intensities of all lines that have arelative intensity of >9% in the sample for atorvastatin morpholine andhydrates thereof:

TABLE 15 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN MORPHOLINE AND HYDRATES THEREOF Relative Degree Intensity2θ (>9%) 4.8 15.9 5.7 10.7 6.4 11.6 8.6 9.2 9.7 52.5 12.8 6.8 14.1 10.314.6 22.5 16.0 42.1 16.3 26.7 16.5 21.3 17.3 19.6 17.5 29.3 18.1 16.518.9 46.1 19.2 27.3 19.6 85.9 19.9 19.8 20.8 42.2 21.2 16.9 22.1 89.923.1 19.6 23.9 100.0 24.6 26.0 25.0 39.0 25.7 11.0 27.0 14.1 28.1 10.128.5 25.8 29.6 11.8 30.1 9.9 30.9 13.4 31.0 14.1 32.0 13.0 32.4 16.533.4 14.1 33.9 11.0 34.6 18.0 35.4 14.3 36.8 18.2 37.6 11.4

Table 16 lists individual 2θ peaks for atorvastatin morpholine andhydrates thereof:

TABLE 16 ATORVASTATIN MORPHOLINE AND HYDRATES THEREOF Degree 2θ 9.7 16.018.9 19.6 20.8 22.1 23.9 25.0

Table 17 lists the 2θ and relative intensities of all lines that have arelative intensity of >15% in the sample for atoraystatin olamine andhydrates thereof:

TABLE 17 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN OLAMINE AND HYDRATES THEREOF Relative Degree Intensity 2θ(>15%) 8.5 100.0 9.8 74.7 11.4 17.3 12.0 15.6 16.3 27.7 17.4 43.9 18.685.5 19.6 45.8 20.1 43.9 20.9 96.0 21.4 31.6 22.0 30.5 22.5 66.1 22.835.6 23.5 20.5 24.1 42.7 25.1 23.3 25.9 25.0 26.2 33.1 27.8 19.3 28.827.5 29.6 20.0 31.7 20.5 37.7 22.5

Table 18 lists individual 2θ peaks for atorvastatin olamine and hydratesthereof:

TABLE 18 ATORVASTATIN OLAMINE AND HYDRATES THEREOF Degree 2θ 8.5 9.817.4 18.6 20.9 22.5 24.1

Table 19 lists the 2θ and relative intensities of all lines that have arelative intensity of >20% in the sample for atorvastatin piperazine andhydrates thereof:

TABLE 19 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN PIPERAZINE AND HYDRATES THEREOF Relative Degree Intensity2θ (>20%) 4.4 20.4 7.8 25.5 9.3 27.2 11.8 29.7 13.2 22.9 16.1 30.0 17.730.9 19.7 100.0 20.4 55.0 22.2 31.9 22.9 36.2 23.8 30.7 26.4 32.6

Table 20 lists the individual 2θ peaks for atorvastatin piperazine andhydrates thereof:

TABLE 20 ATORVASTATIN PIPERAZINE AND HYDRATES THEREOF Degree 2θ 7.8 9.311.8 16.1 19.7

Table 21 lists the 2θ and relative intensities of all lines that have arelative intensity of >25% in the sample for atoravastatin sodium andhydrates thereof:

TABLE 21 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN SODIUM AND HYDRATES THEREOF Relative Degree Intensity 2θ(>25%) 3.4 57.8 4.1 29.2 4.9 53.0 5.6 32.4 6.8 25.2 7.6 68.5 8.0 75.78.5 42.0 9.9 66.1 10.4 51.5 12.8 25.5 18.9 100.0 19.7 64.5 21.2 32.822.1 33.3 22.9 45.4 23.3 43.6 24.0 42.7 25.2 26.1

Table 22 lists individual 2θ peaks for atorvastatin sodium and hydratesthereof:

TABLE 22 ATORVASTATIN SODIUM AND HYDRATES THEREOF Degree 2θ 3.4 4.9 7.68.0 9.9 18.9 19.7

Table 23 lists the 2θ and relative intensities of all lines that have arelative intensity of >25% in the sample for atorvastatin2-amino-2-methylpropan-1-ol and hydrates thereof:

TABLE 23 INTENSITIES AND PEAK LOCATIONS OF DIFFRACTION LINES FORATORVASTATIN 2-AMINO-2- METHYLPROPAN-1-OL AND HYDRATES THEREOF RelativeDegree Intensity 2θ (>20%) 4.2 95.2 6.0 59.9 6.2 43.7 8.3 26.3 11.5 20.912.5 36.5 12.6 31.1 16.0 44.4 17.5 54.3 18.3 52.8 18.8 34.0 19.4 55.319.7 100.0 21.3 26.7 22.0 31.3 22.8 21.7 23.4 29.7 23.8 28.6

Table 24 lists individual peaks for atorvastatin2-amino-2-methylpropan-1-ol and hydrates thereof:

TABLE 24 ATORVASTATIN 2-AMINO-2-METHYLPROPAN-1-OL AND HYDRATES THEREOFDegree 2θ 4.2 8.3 16.0 17.5 18.3 19.4 19.7

Solid State Nuclear Magnetic Resonance

The novel salt forms of atorvastatin may also be characterized by theirsolid-state nuclear magnetic resonance spectra. Thus, the solid-statenuclear magnetic resonance spectra of the salt forms of atorvastatinwere carried out on a Bruker-Biospin Avance DSX 500 MHz NMRspectrometer.

¹⁹F SSNMR

Approximately 15 mg of sample were tightly packed into a 2.5 mm ZrOspinner for each sample analyzed. One-dimensional ¹⁹F spectra werecollected at 295 K and ambient pressure on a Bruker-Biospin 2.5 mm BLcross-polarization magic angle spinning (CPMAS) probe positioned into awide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. Thesamples were positioned at the magic angle and spun at 35.0 kHz with nocross-polarization from protons, corresponding to the maximum specifiedspinning speed for the 2.5 mm spinners. The fast spinning speedminimized the intensities of the spinning side bands and provided almostcomplete decoupling of ¹⁹F signals from protons. The number of scanswere individually adjusted for each sample to obtain adequatesingle/noise (S/N). Typically, 150 scans were acquired. Prior to ¹⁹Facquisition, ¹⁹F relaxation times were measured by an inversion recoverytechnique. The recycle delay for each sample was then adjusted to fivetimes the longest ¹⁹F relaxation time in the sample, which ensuredacquisition of quantitative spectra. A fluorine probe background wassubtracted in each alternate scan after presaturating the ¹⁹F signal.The spectra were referenced using an external sample of trifluoroaceticacid (diluted to 50% V/V by H₂O), setting its resonance to −76.54 ppm.

¹³C SSNMR

Approximately 80 mg of sample were tightly packed into a 4 mm ZrOspinner for each sample analyzed. One-dimensional ¹³C spectra werecollected at ambient pressure using ¹H-¹³C CPMAS at 295 K on a Bruker 4mm BL CPMAS probe positioned into a wide-bore Bruker-Biospin Avance DSX500 MHZ NMR spectrometer. The samples were spun at 15.0 kHzcorresponding to the maximum specified spinning speed for the 7 mmspinners. The fast spinning speed minimized the intensities of thespinning side bands. To optimize the signal sensitivity, thecross-polarization contact time was adjusted to 1.5 ms, and the protondecoupling power was set to 100 kHz. The number of scans wereindividually adjusted for each sample to obtain adequate S/N. Typically,1900 scans were acquired with a recycle delay of 5 seconds. The spectrawere referenced using an external sample of adamantane, setting itsupfield resonance at 29.5 ppm.

Table 25 and Table 25a lists the ¹³C NMR chemical shifts for Form A andB atorvastatin benethamine and hydrates thereof:

TABLE 25 FORM A BENETHAMINE AND HYDRATES THEREOF Peak # ppm* 1 180.1 2178.8 3 165.1 4 164.1 5 162.8 6 161.7 7 160.7 8 140.6 9 139.6 10 137.911 136.1 12 133.0 13 129.6 14 127.3 15 126.4 16 125.4 17 123.1 18 122.519 121.6 20 121.1 21 119.9 22 116.4 23 115.4 24 114.5 25 114.0 26 66.027 65.5 28 64.6 29 53.6 30 51.5 31 51.0 32 47.8 33 44.6 34 43.3 35 41.436 40.9 37 38.5 38 37.7 39 36.8 40 34.0 41 32.7 42 26.5 43 25.1 44 23.545 23.1 46 19.7 47 19.1 *Values in ppm with respect to trimethylsilane(TMS) at 0 ppm; referenced using an external sample of adamantane,setting is upfield resonance to 29.5 ppm.

TABLE 25a FORM B BENETHAMINE AND HYDRATES THEREOF Peak # ppm* 1 179.4 2165.6 3 162.4 4 140.1 5 138.6 6 133.6 7 132.8 8 129.9 9 128.2 10 125.711 123.6 12 114.8 13 69.6 14 69.0 15 52.3 16 49.8 17 43.1 18 42.2 1939.6 20 38.9 21 31.5 22 26.5 23 23.5 24 19.6 *Values in ppm with respectto trimethylsilane (TMS) at 0 ppm; referenced using an external sampleof adamantane, setting is upfield resonance to 29.5 ppm.

Table 26 lists individual ¹³C NMR chemical shifts for Form Aatorvastatin benethamine:

TABLE 26 FORM A ATORVASTATIN BENETHAMINE AND HYDRATES THEREOF Peak #ppm* 1 180.1 2 178.8 3 165.1 4 164.1 5 161.7 6 160.7 7 26.5 8 25.1 923.5 10 23.1 11 19.7 12 19.1 *Values in ppm with respect totrimethylsilane (TMS) at 0 ppm; referenced using an external sample ofadamantane, setting isupfield resonance to 29.5 ppm.

Table 27 lists individual ¹³C NMR chemical shifts for Form Batorvastatin benethamine:

TABLE 27 FORM B ATORVASTATIN BENETHAMINE AND HYDRATES THEREOF Peak #ppm* 1 179.4 2 165.6 22 26.5 23 23.5 24 19.6 *Values in ppm with respectto trimethylsilane (TMS) at 0 ppm; referenced using an external sampleof adamantane, setting is upfield resonance to 29.5 ppm.

Table 28 and 28a lists the ¹⁹F NMR chemical shifts for Forms A and Batorvastatin benethamine and hydrates thereof:

TABLE 28 FORM A ATORVASTATIN BENETHAMINE AND HYDRATES THEREOF Peak #ppm* 1 −113.2 2 −114.2 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

TABLE 28a FORM B ATORVASTATIN BENETHAMINE AND HYDRATES THEREOF Peak #ppm* 1 −113.7 2 −114.4 *Values in ppm with respect to CCl₃F at 0 ppm,referenced using an external standard of trifluoroacetic acid (50% V/Vin water) at −76.54 ppm.

Table 29 lists the ¹³C NMR chemical shifts for atorvastatindibenzylamine and hydrates thereof:

TABLE 29 ATORVASTATIN DIBENZYLAMINE AND HYDRATES THEREOF Peak # ppm* 1179.1 2 166.2 3 163.1 4 160.8 5 140.6 6 135.2 7 134.3 8 133.4 9 131.9 10131.1 11 129.4 12 128.3 13 125.6 14 124.2 15 122.9 16 119.7 17 115.4 1869.7 19 68.6 20 52.6 21 51.3 22 43.0 23 41.9 24 38.8 25 38.2 26 26.7 2723.3 28 20.0 *Values in ppm with respect to trimethylsilane (TMS) at 0ppm; referenced using an external sample of adamantane, setting isupfield resonance to 29.5 ppm.

Table 30 lists individual ¹³C NMR chemical shifts for atorvastatindibenzylamine and hydrates thereof:

TABLE 30 ATORVASTATIN DIBENZYLAMINE AND HYDRATES THEREOF Peak # ppm* 1179.1 2 166.2 3 163.1 4 160.8 26 26.7 27 23.3 28 20.0 *Values in ppmwith respect to trimethylsilane (TMS) at 0 ppm; referenced using anexternal sample of adamantane, setting is upfield resonance to 29.5 ppm.

Table 31 lists the ¹⁹F NMR chemical shifts for atorvastatindibenzylamine and hydrates thereof:

TABLE 31 ATORVASTATIN DIBENZYLAMINE AND HYDRATES THEREOF Peak # ppm* 1−107.8 *Values in ppm with respect to CCl₃F at 0 ppm, referenced usingan external standard of trifluoroacetic acid (50% V/V in water) at−76.54 ppm.

Table 32 lists the ¹³C NMR chemical shifts for atorvastatin erbumine andhydrates thereof:

TABLE 32 ATORVASTATIN ERBUMINE AND HYDRATES THEREOF Peak # ppm* 1 179.32 164.5 3 163.0 4 160.9 5 141.3 6 140.9 7 135.3 8 134.5 9 132.8 10 129.011 127.7 12 124.5 13 121.8 14 120.2 15 116.5 16 115.5 17 112.4 18 71.319 50.3 20 47.7 21 42.6 22 41.0 23 28.5 24 26.4 25 22.6 26 21.6 *Valuesin ppm with respect to trimethylsilane (TMS) at 0 ppm; referenced usingan external sample of adamantane, setting is upfield resonance to 29.5ppm.

Table 33 lists individual ¹³C NMR chemical shifts for atorvastatinerbumine and hydrates thereof:

TABLE 33 ATORVASTATIN ERBUMINE AND HYDRATES THEREOF Peak # ppm* 1 179.32 164.5 3 163.0 4 160.9 23 28.5 24 26.4 25 22.6 26 21.6 *Values in ppmwith respect to trimethylsilane (TMS) at 0 ppm; referenced using anexternal sample of adamantane, setting is upfield resonance to 29.5 ppm.

Table 34 lists the ¹⁹F NMR chemical shifts for atorvastatin erbumine andhydrates thereof:

TABLE 34 ATORVASTATIN ERBUMINE AND HYDRATES THEREOF Peak # ppm* 1 −110.4*Values in ppm with respect to CCl₃F at 0 ppm, referenced using anexternal standard of trifluoroacetic acid (50% V/V in water) at −76.54ppm.

Table 35 lists the ¹³C NMR chemical shifts for atorvastatin morpholineand hydrates thereof:

TABLE 35 ATORVASTATIN MORPHOLINE AND HYDRATES THEREOF Peak # ppm* 1179.3 2 165.9 3 162.7 4 160.5 5 139.6 6 137.8 7 134.3 8 131.2 9 129.6 10128.7 11 127.4 12 122.9 13 120.8 14 117.9 15 116.3 16 70.8 17 69.5 1863.4 19 42.4 20 41.2 21 40.5 22 24.8 23 20.6 *Values in ppm with respectto trimethylsilane (TMS) at 0 ppm; referenced using an external sampleof adamantane, setting is upfield resonance to 29.5 ppm.

Table 36 lists individual ¹³C NMR chemical shifts for atorvastatinmorpholine and hydrates thereof:

TABLE 36 ATORVASTATIN MORPHOLINE AND HYDRATES THEREOF Peak # ppm* 1179.3 2 165.9 4 160.5 22 24.8 23 20.6 *Values in ppm with respect totrimethylsilane (TMS) at 0 ppm; referenced using an external sample ofadamantane, setting is upfield resonance to 29.5 ppm.

Table 37 lists individual ¹⁹F NMR chemical shifts for atorvastatinmorpholine and hydrates thereof:

TABLE 37 ATORVASTATIN MORPHOLINE AND HYDRATES THEREOF Peak # ppm* 1−117.6 *Values in ppm with respect to CCl₃F at 0 ppm, referenced usingan external standard of trifluoroacetic acid (50% V/V in water) at−76.54 ppm.

Table 38 lists the ¹³C NMR chemical shifts for atorvastatin olamine andhydrates thereof:

TABLE 38 ATORVASTATIN OLAMINE AND HYDRATES THEREOF Peak # ppm* 1 182.0 2178.9 3 165.4 4 161.6 5 159.5 6 137.4 7 134.8 8 133.8 9 131.0 10 128.711 128.0 12 127.0 13 123.1 14 122.6 15 121.9 16 120.9 17 120.1 18 117.319 115.6 20 114.3 21 66.5 22 66.0 23 65.2 24 58.5 25 58.2 26 51.1 2747.8 28 46.0 29 43.9 30 42.4 31 41.3 32 40.6 33 39.8 34 25.7 35 23.1 3621.1 37 20.7 *Values in ppm with respect to trimethylsilane (TMS) at 0ppm; referenced using an external sample of adamantane, setting isupfield resonance to 29.5 ppm.

Table 39 lists the individual ¹³C NMR chemical shifts for atorvastatinolamine and hydrates thereof:

TABLE 39 ATORVASTATIN OLAMINE AND HYDRATES THEREOF Peak # PPM# 1 182.0 2178.9 3 165.4 4 161.6 5 159.5 34 25.7 35 23.1 36 21.1 37 20.7 *Values inppm with respect to trimethylsilane (TMS) at 0 ppm; referenced using anexternal sample of adamantane, setting is upfield resonance to 29.5 ppm.

Table 40 lists the ¹⁹F NMR chemical shifts for atorvastatin olamine andhydrates thereof:

TABLE 40 ATORVASTATIN OLAMINE AND HYDRATES THEREOF Peak # ppm* 1 −118.7*Values in ppm with respect to CCl₃F at 0 ppm, referenced using anexternal standard of trifluoroacetic acid (50% V/V in water) at −76.54ppm.

Table 41 lists the ¹³C NMR chemical shifts for atorvastatin2-amino-2-methyl-propan-1-ol and hydrates thereof:

TABLE 41 ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1-OL AND HYDRATES THEREOFPeak # ppm* 1 179.8 2 166.3 3 163.3 4 161.5 5 161.2 6 140.5 7 139.5 8134.4 9 132.3 10 131.6 11 129.8 12 128.1 13 126.1 14 125.1 15 122.2 16120.7 17 116.4 18 114.0 19 113.4 20 72.6 21 71.4 22 67.6 23 66.3 24 64.725 64.4 26 53.1 27 46.9 28 43.9 29 43.5 30 42.7 31 39.7 32 36.1 33 26.834 26.3 35 24.3 36 23.8 37 23.1 38 22.0 39 20.4 *Values in ppm withrespect to trimethylsilane (TMS) at 0 ppm; referenced using an externalsample of adamantane, setting is upfield resonance to 29.5 ppm.

Table 42 lists individual ¹³C NMR chemical shifts for atorvastatin2-amino-2-methyl-propan-1-ol and hydrates thereof:

TABLE 42 ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1-OL AND HYDRATES THEREOFPeak # ppm* 1 179.8 2 166.3 3 163.3 38 22.0 39 20.4 *Values in ppm withrespect to trimethylsilane (TMS) at 0 ppm; referenced using an externalsample of adamantane, setting is upfield resonance to 29.5 ppm.

Table 43 lists the ¹⁹F NMR chemical shifts for atorvastatin2-amino-2-methyl-propan-1-ol and hydrates thereof:

TABLE 43 ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1-OL AND HYDRATES THEREOFPeak # ppm* 1 −113.6 2 −116.5 *Values in ppm with respect to CCl₃F at 0ppm, referenced using an external standard of trifluoroacetic acid (50%V/V in water) at −76.54 ppm.

Additionally, Form A & B atorvastatin benethamine, atorvastatindibenzylamine, atorvastatin erbumine, atorvastatin morpholine,atorvastatin olamine, and atorvastatin 2-amino-2-methyl-propan-1-ol or ahydrate thereof of the aforementioned salts may be characterized by anx-ray powder diffraction pattern or a solid state ¹⁹F nuclear magneticresonance spectrum. For example:

An atorvastatin ammonium or hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 7.8, 8.8, 9.3, 9.9, 10.6, 12.4, and 19.5.

A Form A atorvastatin benethamine or hydrate thereof having an x-raypowder diffraction pattern containing the following 2θ peaks measuredusing CuK_(α) radiation: 4.7, 5.3, 9.5, 12.0, 15.6, 18.1, and 19.9, or asolid state ¹⁹F nuclear magnetic resonance having the following chemicalshifts expressed in parts per million: −113.2 and −114.2.

A Form B atorvastatin benethamine or hydrate thereof having an x-raypowder diffraction pattern containing the following 2θ peaks measuredusing CuK_(α) radiation: 5.0, 7.1, 8.4, 10.0, 11.6, 12.6, 14.8, and20.2, or a solid state ¹⁹F nuclear magnetic resonance having thefollowing chemical shifts expressed in parts per million: −113.7 and−114.4.

A Form A atorvastatin benzathine or hydrate thereof having an x-raypowder diffraction pattern containing the following 2θ peaks measuredusing CuK_(α) radiation: 14.0 and 15.1.

A Form B atorvastatin benzathine or hydrate thereof having an x-raypowder diffraction pattern containing the following 2θ peaks measuredusing CuK_(α) radiation: 8.3, 10.2, 14.4, 15.8, 18.6, 21.8, and 23.3.

A Form C atorvastatin benzathine or hydrate thereof having an x-raypowder diffraction pattern containing the following 2θ peaks measuredusing CuK_(α) radiation: 3.9, 6.9, 7.9, 9.7, and 12.8.

An atorvastatin dibenzylamine or hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 8.3, 18.7, 19.8, 20.7, 21.3, and 25.8, or a solidstate ¹⁹F nuclear magnetic resonance having the following chemicalshifts expressed in parts per million: −107.8.

A compound selected from the group consisting of:

-   -   (a) Form A atorvastatin diethylamine or hydrate thereof having        an x-ray powder diffraction pattern containing the following 2θ        peaks measured using CuK_(α) radiation: 17.0, 18.2, 20.0, 21.7,        and 23.0; and    -   (b) Form B atorvastatin diethylamine or a hydrate thereof having        an x-ray powder diffraction pattern containing the following 2θ        peaks measured using CuK_(α) radiation: 6.1, 11.5, 15.3, 17.4,        20.5, 23.2, and 27.6.

An atorvastatin erbumine or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 5.4, 7.3, 9.5, 17.8, 19.2, 20.0, 22.2, and 24.2, or asolid state ¹⁹F nuclear magnetic resonance having the following chemicalshifts expressed in parts per million: −110.4.

An atorvastatin L-lysine or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 6.7, 9.8, 17.1, and 24.0.

An atorvastatin morpholine or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 9.7, 16.0, 18.9, 19.6, 20.8, 22.1, 23.9, and 25.0, ora solid state ¹⁹F nuclear magnetic resonance having the followingchemical shifts expressed in parts per million: −117.6.

An atorvastatin olamine or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 8.5, 9.8, 17.4, 18.6, 20.9, 22.5, and 24.1, or asolid state ¹⁹F nuclear magnetic resonance having the following chemicalshifts measured in parts per million: −118.7.

An atorvastatin piperazine or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 7.8, 9.3, 11.8, 16.1, and 19.7.

An atorvastatin sodium or a hydrate thereof having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuK_(α) radiation: 3.4, 4.9, 7.6, 8.0, 9.9, 18.9, and 19.7.

An atorvastatin 2-amino-2-methylpropan-1-ol or a hydrate thereof havingan x-ray powder diffraction pattern containing the following 2θ peaksmeasured using CuK_(α) radiation: 4.2, 8.3, 16.0, 17.5, 18.3, 19.4, and19.7, or a solid state ¹⁹F nuclear magnetic resonance having thefollowing chemical shifts measured in parts per million: −113.6 and−116.5.

The salt forms of atorvastatin of the present invention, regardless ofthe extent of hydration and/or solvation having equivalent x-ray powderdiffractograms, or SSNMR, are within the scope of the present invention.

The new salt forms of atorvastatin described herein have advantageousproperties. For example, the benethamine, benzathine, dibenzylamine,diethylamine, erbumine, and morpholine salts were determined to beanhydrous, high melting as well as considered to be non-hygroscopiccompounds. The olamine and 2-amino-2-methylpropan-1-ol salts weredetermined to be anhydrous and high melting as well. Also, thediethylamine, erbumine, morpholine, olamine, and2-amino-2-methylpropan-1-ol salts of atorvastatin exhibited higheraqueous solubility compared to Form I atorvastatin calcium (disclosed inU.S. Pat. No. 5,969,156).

The present invention provides a process for the preparation of the saltforms of atorvastatin which comprises preparing a solution ofatorvastatin free acid (U.S. Pat. No. 5,213,995) in one of the followingsolvents: acetone, acetonitrile, THF, 1:1 acetone/water (v/v),isopropanol (IPA), or chloroform. The cationic counterion solutions wereprepared using either 0.5 or 1.0 equivalent in the same solvent. Waterwas added to some counterions to increase their solubility. Theatorvastatin free acid solution was added to the counterion solutionwhile stirring. The reaction was stirred for at least 48 hours atambient temperature. Samples containing solids were vacuum filtered,washed with the reaction solvent, and air-dried overnight at ambientconditions. If precipitation was not present after ˜2 weeks, thesolution was slowly evaporated. All samples were stored at ambienttemperature and characterized as described hereinafter.

TABLE 44 Structure of Counterions used in the preparation ofAtorvastatin salts. Common Structure Name Name ⁺NH₄ Ammonium Ammonium

N-benzyl-2-Phenylethylamine Benethamine

N,N′-Bis(phenylmethyl)-1,2- ethanediamine Benzathine

N-(Phenylmethyl) benzenemethanamine Dibenzylamine

N-Ethylethanamine Diethylamine

tert-butylamine Erbumine

(S)-2,6-diaminohexanoic acid L-Lysine

Tetrahydro-2H-1,4-oxazine Morpholine

2-aminoethanol Olamine Na Sodium Sodium

Hexahydropyrazine Piperazine

2,2-Diethylethanolamine 2-amino-2methylpropan- 1-ol

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from two or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.5 mg to 100 mg, preferably 2.5 mg to 80 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as hypolipidemic and/or hypocholesterolemic agentsand agents to treat osteoporosis, benign prostatic hyperplasia, andAlzheimer's disease, the salt forms of atorvastatin utilized in thepharmaceutical method of this invention are administered at the initialdosage of about 2.5 mg to about 80 mg daily. A daily dose range of about2.5 mg to about 20 mg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, ammonium salt (atorvastatin ammonium)

The ammonium salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inacetonitrile (ACN) (0.634 g in 25 mL of ACN). A solution was prepared bydissolving 12.04 mg of ammonium hydroxide (1.0 equivalents) inacetonitrile (0.5 mL). The stock solution of atorvastatin free acid(2.24 mL) was added to the counterion solution with stirring. If a gelformed, additional acetonitrile and water was added as necessary. After2 days of stirring at ambient temperature, the solids were isolated byvacuum filtration using a 0.45 μm nylon 66 membrane filter. The solidswere rinsed with acetonitrile and air dried at ambient conditions toafford atorvastatin ammonium.

EXAMPLE 2[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, N-benzyl-2-phenylethylamine (atorvastatin benethamine)

Method A: The benethamine salt of atorvastatin (Form A) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofN-benzyl-2-phenylethylamine (benethamine) was prepared by dissolving378.59 mg (1.0 equivalents) in acetonitrile (10 mL). The stock solutionof atorvastatin free acid was added to the counterion solution withstirring. Over time, an additional 40 mL of acetonitrile was added toprevent the formation of a gel. After 5 days of stirring at ambienttemperature, the solids were isolated by vacuum filtration using aBuchner funnel fitted with a paper filter (#2 Whatman). The solids wererinsed with acetonitrile (75 mL), and placed in a 25° C. oven undernitrogen to dry overnight to afford atorvastatin benethamine Form A.

Method B: The benethamine salt of atorvastatin (Form B) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in 2-propanol (IPA) (1 g in 40 mL of IPA). Asolution of N-benzyl-2-phenylethylamine (benethamine) was prepared bydissolving 388.68 mg (1.1 equivalents) in 2-propanol (100 mL). The stocksolution of atorvastatin free acid was added to the counterion solutionwith stirring. Seed crystals of the benethamine salt were added. Themixture was reduced to a wet solid under a nitrogen bleed, and theresulting solids were slurried in 2-propanol (40 mL). After 7 days ofstirring at ambient temperature, the solids were isolated by vacuumfiltration using a Buchner funnel fitted with a paper filter (#2Whatman). The solids were rinsed with 2-propanol (25 mL), and placed ina 25° C. oven under nitrogen to dry overnight to afford atorvastatinbenethamine Form B.

EXAMPLE 3[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid,N,N¹-bis(phenylmethyl)-1,2-ethanediamine (atorvastatin benzathine)

Method A: The benzathine salt of atorvastatin (Form A) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofN,N′-bis(phenylmethyl)-1,2-ethanediamine (benzathine) was prepared bydissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water(20 mL). The stock solution of atorvastatin free acid was added to thecounterion solution with stirring. After 2 days of stirring at ambienttemperature, the solids were isolated by vacuum filtration using aBuchner funnel fitted with a paper filter (#2 Whatman). The solids wererinsed with acetonitrile (75 mL), and placed in a 25° C. oven undernitrogen to dry overnight to afford benzathine Form A.

Method B: The benzathine salt of atorvastatin (Form B) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofN,N′-bis(phenylmethyl-1,2-ethanediamine (benzathine) was prepared bydissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water(20 mL). The stock solution of atorvastatin free acid was added to thecounterion solution with stirring. After 2 days of stirring at ambienttemperature, the solids were isolated by vacuum filtration using aBuchner funnel fitted with a paper filter (#2 Whatman). The solids wererinsed with acetonitrile (75 mL) to afford atorvastatin benzathine FormB. Note that this procedure is the same as above except that the samplewas not oven dried.

Method C: The benzathine salt of atorvastatin (Form C) was synthesizedby adding Form A atorvastatin benzathine to 3 mL of deionized water inexcess of its solubility. The slurry was stirred at room temperature for2 days, isolated by vacuum filtration, and dried under ambientconditions to yield atorvastatin benzathine Form C.

EXAMPLE 4[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid,N-(phenylmethyl)benzenemethanamine (atorvastatin dibenzylamine)

The dibenzylamine salt of atorvastatin was synthesized by preparing astock solution of the free acid of atorvastatin (U.S. Pat. No.5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofdibenzylamine was prepared by dissolving 351.05 mg (1.0 equivalents) inacetonitrile (100 mL). The stock solution of atorvastatin free acid wasadded to the counterion solution with stirring. Overtime, additionalacetonitrile was added to prevent formation of a gel (100 mL), and thesolid was allowed to stir. After 4 days of stirring at ambienttemperature, the solids were isolated by vacuum filtration using aBuchner funnel fitted with a paper filter (#2 Whatman). The solids wererinsed with acetonitrile (75 mL), and placed in a 25° C. oven undernitrogen to dry overnight to afford atorvastatin dibenzylamine.

EXAMPLE 5[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid,N-ethylethanamine (atorvastatin diethylamine)

Method A: The diethylamine salt of atorvastatin (Form A) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofdiethylamine was prepared by dissolving 132.33 mg (1.0 equivalents) inacetonitrile (20 mL). The stock solution of atorvastatin free acid wasadded to the counterion solution with stirring. Over time, an additional40 mL of acetonitrile was added to prevent the formation of a gel. After5 days of stirring at ambient temperature, the solids were isolated byvacuum filtration using a Buchner funnel fitted with a paper filter (#2Whatman). The solids were rinsed with acetonitrile (75 mL), and placedin a 25° C. oven under nitrogen to dry overnight to afford atorvastatindiethylamine Form A.

Method B: The diethylamine salt of atorvastatin (Form B) was synthesizedby preparing a stock solution of the free acid of atorvastatin (U.S.Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution ofdiethylamine was prepared by dissolving 132.33 mg (1.0 equivalents) inacetonitrile (20 mL). The stock solution of atorvastatin free acid wasadded to the counterion solution with stirring. Over time, an additional40 mL of acetonitrile was added to prevent the formation of a gel. After5 days of stirring at ambient temperature, the solids were isolated byvacuum filtration using a Buchner funnel fitted with a paper filter (#2Whatman). The solids were rinsed with acetonitrile (75 mL) to affordatorvastatin diethylamine Form B. Note that this procedure is the sameas above except that the sample was not oven dried.

EXAMPLE 6[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, tertiary-butylamine (atorvastatin erbumine)

The erbumine salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inacetonitrile (1 g in 40 mL of ACN). A solution of tert-butylamine(erbumine) was prepared by dissolving 128.00 mg (1.0 equivalents) inacetonitrile (10 mL). The stock solution of atorvastatin free acid wasadded to the counterion solution with stirring. Over time, an additional120 mL of acetonitrile was added to prevent the formation of a gel.After 5 days of stirring at ambient temperature, the solids wereisolated by vacuum filtration using a Buchner funnel fitted with a paperfilter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL),and placed in a 25° C. oven under nitrogen to dry overnight to affordatorvastatin erbumine.

EXAMPLE 7[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, L-lysine (atorvastatin L-lysine)

The L-lysine salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inisopropyl alcohol (IPA) (2.577 g in 50 mL of IPA). A solution ofL-lysine was prepared by dissolving 28.0 mg (1.0 equivalents) inisopropyl alcohol (1 mL). The stock solution of atorvastatin free acid(2.08 mL) was added to the counterion solution with stirring. After 7days of stirring at ambient temperature, the solids were isolated byvacuum filtration using a 0.45 μm nylon 66 membrane filter. The solidswere rinsed with IPA and allowed to air dry at ambient temperature toafford L-lysine.

EXAMPLE 8[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, tetrahydro-2H-1,4-oxazine (atorvastatin morpholine)

The morpholine salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inacetonitrile (1 g in 40 mL of ACN). A solution of morpholine wasprepared by dissolving 160.28 mg (1.1 equivalents) in acetonitrile (100mL). The stock solution of atorvastatin free acid was added to thecounterion solution with stirring. No salt formed, so the solution wasevaporated under N₂ until a white solid formed. Acetonitrile was thenadded to the solid (50 mL), and the solid was allowed to stir. After 3days of stirring at ambient temperature, the solids were isolated byvacuum filtration using a Buchner funnel fitted with a paper filter (#2Whatman). The solids were rinsed with acetonitrile (25 mL), and placedin a 25° C. oven under nitrogen to dry overnight to afford atorvastatinmorpholine.

EXAMPLE 9[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, 2-aminoethanol (atorvastatin olamine)

Method A—The olamine salt of atorvastatin was synthesized by preparing astock solution of the free acid of atorvastatin (U.S. Pat. No.5,273,995) in acetonitrile (0.8 g in 25 mL of ACN). A solution ofolamine was prepared by dissolving 15.0 mg of olamine (˜2.7 equivalents)in 0.5 mL of acetonitrile. The stock solution of atorvastatin free acid(3.0 mL) was added to the counterion solution with stirring. If a gelformed, additional acetonitrile was added as necessary. After 6 days ofstirring at ambient temperature, the solids were isolated by vacuumfiltration using a 0.45 μm nylon 66 membrane filter. The solids wererinsed with acetonitrile and air dried at ambient conditions to affordatorvastatin olamine.

Method B—The olamine salt of atorvastatin was synthesized by preparing astock solution of the free acid of atorvastatin (U.S. Pat. No.5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of2-aminoethanol (olamine) was prepared by dissolving 139.77 mg (1.1equivalents) in acetonitrile (100 mL).

The stock solution of atorvastatin free acid was added to the counterionsolution with stirring. Seed crystals of the olamine salt were added.Over time, additional acetonitrile was added to aid in stirring (300mL), and the solid was allowed to stir. After 4 days of stirring atambient temperature, the solids were isolated by vacuum filtration usinga Buchner funnel fitted with a paper filter (#2 Whatman). The solidswere rinsed with acetonitrile (75 mL), and placed in a 25° C. oven undernitrogen to dry for two days to afford atorvastatin olamine.

EXAMPLE 10[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, piperazine (atorvastatin piperazine)

The piperazine salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inisopropyl alcohol (2.577 g in 50 mL of IPA). A solution of piperazinewas prepared by dissolving 14.4 mg (1.0 equivalents) in isopropylalcohol (1 mL). The stock solution of atorvastatin free acid (1.85 mL)was added to the counterion solution with stirring. After 7 days ofstirring at ambient temperature, the solids were isolated by vacuumfiltration using a 0.45 μm nylon 66 membrane filter. The solids wererinsed with isopropyl alcohol and air dried at ambient conditions toafford atorvastatin piperazine.

EXAMPLE 11[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, sodium (atorvastatin sodium)

The sodium salt of atorvastatin was synthesized by preparing a stocksolution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) inacetonitrile (0.634 g in 25 mL of ACN). A solution was prepared bydissolving 2.67 mg of sodium hydroxide (1.0 equivalents) in 0.5 mL ofacetonitrile and 0.05 mL of water. The stock solution of atorvastatinfree acid (1.55 mL) was added to the counterion solution with stirring.If a gel formed, additional acetonitrile and water was added asnecessary. After 6 days of stirring at ambient temperature, the solidswere isolated by vacuum filtration using a 0.45 μm nylon 66 membranefilter. The solids were rinsed with acetonitrile and air dried atambient conditions to afford atorvastatin sodium.

EXAMPLE 12[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, 2-amino-2-methylpropan-1-ol (atorvastatin2-amino-2-methylpropan-1-ol)

Method A—The 2-amino-2-methylpropan-1-ol salt of atorvastatin wassynthesized by preparing a stock solution of the free acid ofatorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (0.8 g in 25 mLof ACN). A solution of 2-amino-2-methylpropan-1-ol was prepared bydissolving 6.1 mg of 2-amino-2-methylpropan-1-ol (1 equivalents) in 0.5mL of acetonitrile. The stock solution of atorvastatin free acid (1.21mL) was added to the counterion solution with stirring. If a gel formed,additional acetonitrile was added as necessary. After 6 days of stirringat ambient temperature, the solids were isolated by vacuum filtrationusing a 0.45 μm nylon 66 membrane filter. The solids were rinsed withacetonitrile and air dried at ambient conditions to afford atoravastatin2-amino-2-methylpropan-1-ol.

Method B—The 2-amino-2-methylpropan-1-ol salt of atorvastatin wassynthesized by preparing a stock solution of the free acid ofatorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL ofACN). A solution of 2-amino-2-methylpropan-1-ol was prepared bydissolving 173.08 mg (1.1 equivalents) in acetonitrile (100 mL). Thestock solution of atorvastatin free acid was added to the counterionsolution with stirring. Seed crystals of the 2-amino-2-methylpropan-1-olsalt were added. Over time, additional acetonitrile was added to aid instirring (100 mL), and the solid was allowed to stir. After 4 days ofstirring at ambient temperature, the solids were isolated by vacuumfiltration using a Buchner funnel fitted with a paper filter (#2Whatman). The solids were rinsed with acetonitrile (75 mL), and placedin a 25° C. oven under nitrogen to dry for two days to affordatorvastatin 2-amino-2-methylpropan-1-ol.

What is claimed is:
 1. An atorvastatin piperazine having an x-ray powderdiffraction pattern containing the following 2θ peaks measured usingCuKαradiation: 7.8, 9.3, 11.8, 16.1, and 19.7.
 2. An atorvastatinpiperazine having an x-ray powder diffraction pattern containing thefollowing 2θ peaks measured using CuKα radiation: 4.4, 7.8, 9.3, 11.8,13.2, 16.1, 17.7, 19.7, 20.4, 22.2, 22.9, 23.8 and 26.4.